Università Cattolica del Sacro Cuore

Gruppo della ricerca farmacologia dell'aterotrombosi

GRUPPO DI RICERCA SULLA FARMACOLOGIA DELL’ATEROTROMBOSI
RESEARCH GROUP ON PHARMACOLOGY OF ATHEROTHROMBOSIS

I. The Research Group

Carlo Patrono, MD, Adjunct Professor of Pharmacology

Giovanna Petrucci, BSc, PhD, Assistant Professor of Pharmacology

Bianca Rocca, MD, PhD, Associate Professor of Pharmacology (Group Coordinator)

PhD Students: Francesca De Leva, MD; Paola Ranalli, MD

The main interests of the Research Group are: -) the study of in vivo platelet activation in different clinical settings; -) the variability of the pharmacological response to aspirin and other antiplatelet agents in patients at high cardiovascular risk; -) personalized antithrombotic prophylaxis and combined antithrombotic therapy; -) platelet activation and inhibition in colorectal cancer.

The Group has a large expertise in the field of eicosanoids, antiplatelet drugs and in the in vivo and ex vivo assessment of platelet function, with a special focus on the metabolism of arachidonic acid (AA) via cyclooxygenase (COX)-1 and 2 and on biomarkers related to in vivo prostanoid metabolism.

II. Ongoing Research Projects (2014- present)

- Measurement of in vivo thromboxane A2 biosynthesis as a biomarker of macrovascular thrombotic, bleeding and cancer complications in type 2 diabetes. This project is a sub-study of the trial: ’A Study of Cardiovascular Events in Diabetes’ (ASCEND), in collaboration with the University of Oxford (UK), and had been funded by the European program ‘Innovative Medicines Initiatives (IMI)’ of the Seventh Framework Program. Main aim: to validate on a large cohort the level of platelet activation as predictor of cardiovascular risk.

- Variability in response to aspirin in Myeloproliferative Neoplasms, in collaboration with Prof. Valerio De Stefano (Institute of Hematology, Catholic University School of Medicine, Rome), Dr. Alfredo Dragani (Center for Haemorrhagic, Thrombotic and Rare Hematologic Diseases, Spirito Santo Hospital, Pescara), and with Prof. Raimondo De Cristofaro (Center for Haemorrhagic and Thrombotic Diseases, Catholic University School of Medicine, Rome). Main aim: to personalize the antithrombotic therapy in patients with high platelet turnover

- In silico modeling of aspirin pharmacodynamics, in collaboration with the Department of Bioengineering of the University of Padova, Italy (funded by the European program ‘Innovative Medicines Initiatives (IMI)’ of the Seventh Framework Program). Main aim: to develop in silico modelling supporting clinical trials.

- Aspirin responsiveness in secondary cerebrovascular prevention, in collaboration with Fondazione FADOI Dipartimento per la Ricerca Clinica « Centro Studi FADOI », Milan, Italy. Main aim : understand pharmacological determinants of recurrence in stroke patients.

- Antithrombotic therapy in diabetes and peripheral arterial disease, in collaboration with prof. Dario Pitocco (Diabetolocy Unit, Catholic University School of Medicine, Rome, Italy), Prof. Raimondo De Cristofaro (Center for Haemorrhagic and Thrombotic Diseases, Catholic University School of Medicine, Rome), Prof. Elena Tremoli (Centro Cardiologico Monzino, Milan, Italy). Main aim: investigate the effect of antithrombotic drug combination on in vivo platelet activation, endothelial function and coagulation.

- Expression of cyclooxygenases and in vivo platelet activation in patients with melanoma, in collaboration with Prof.  Ketty Peris (Department of Dermatology, Catholic University School of Medicine, Rome). Main aim: investigate the role of cyclooxygenase expression in cancer progression.

III. Funding

-2018-2019 Catholic University School of Medicine grant ‘Linea D1-2015/2016, for the study: 'Longitudinal analysis of the response to aspirin and non-genetic cardiovascular biomarkers in patients with Polycythaemia Vera and Essential Thrombocythemia. Coordinator: Prof. Bianca Rocca.

-2016-2020 The Agenzia Italiana del Farmaco (AIFA), 'Bando per la Ricerca Indipendente 2012', for the study: 'Novel strategies of antithrombotic prophilaxis in patients with essential thrombocythemia at high risk of cardiovascular events: comparison of different dosing regimens of administration of low-dose acetylsalicylic acid'. Unit Coordinator: Prof. Bianca Rocca. Project Coordinator: Prof. Valerio De Stefano.

2018-2022 Cancer Research UK, "Aspirin for Cancer Prevention Collaboration" Catalyst Grant. Project Coordinators: Prof. Carlo Patrono, Prof. Bianca Rocca

IV. Biosketches

Carlo Patrono, MD, is Adjunct Professor of Pharmacology at the Catholic University School of Medicine in Rome, Italy, and at the Perelman School of Medicine of the University of Pennsylvania in Philadelphia, USA. He trained as a Postdoctoral Fellow in New York with the late Solomon Berson and Nobel Laureate Rosalyn Yalow. Prof. Patrono’s main research interest is in the study of platelet activation and inhibition in atherothrombosis and colorectal cancer. His research has characterized the human pharmacology of aspirin as an inhibitor of platelet cyclooxygenase (COX)-1 and provided the basis for the development of low-dose aspirin as an antithrombotic agent. During the past decade Prof. Patrono has contributed to characterizing the human pharmacology of COX-2 inhibitors and evaluating their cardiovascular effects in different clinical settings.

His international experience includes working for four years in academic institutions in the USA (Mount Sinai School of Medicine, NY and University of Pennsylvania School of Medicine, Philadelphia) and in the UK (King's College and Royal Postgraduate Medical School, London).

He is an elected member of the Association of American Physicians, European Society of Cardiology, Royal College of Physicians, Academia Europaea and Accademia dei Lincei.

He has received the Alexander B. Gutman award from the Mount Sinai School of Medicine, the Distinguished Award in Neuroscience from the Louisiana State University, the 1998 International Aspirin® Award from Bayer AG, the 2007 John Vane Award from the William Harvey Research Institute of the University of London, the 2011 Outstanding Achievement Award of the Eicosanoid Research Foundation (shared with Garret FitzGerald), the 2013 Grand Prix Scientifique de la Fondation Lefoulon-Delalande awarded by the Institut de France (shared with Garret FitzGerald), and the 2013 Lifetime Achievement Award of the European Association for Clinical Pharmacology and Therapeutics (shared with Sir Michael Rawlins).

He is a Section Editor of the Journal of the American College of Cardiology and Associate Editor of the International Journal of Cardiology.

He is a member of the scientific advisory boards of the Dutch Heart Foundation, William Harvey Research Institute, and International Aspirin Foundation.

Prof. Patrono has published over 220 research articles with over 58,000 citations and an h index of 100.


Giovanna Petrucci, BSc, PhD, is Assistant Professor of Pharmacology of the Institute of Pharmacology at the, Catholic University School of Medicine in Rome, Italy. She received her BSc Degree at the University “La Sapienza” of Rome, Italy, in 1998.

From 1999 to 2008 she worked as Research Associate in the Laboratory and Clinical Unit for Immunohistochemistry at the Department of Pathology of the Catholic University of Rome, coordinated by Dr. Nicola Maggiano. From 2008 to 2011 she was PhD Student in the Institute of Pharmacology, Catholic University School of Medicine, Rome, Italy. Under the mentorship of Prof. Carlo Patrono.

 She is a member of the Italian Society of Pharmacology since 2009, and of the Working Group on Thrombosis of 'European Society of Cardiology since 2013.

She has co-authored 25 articles on international journals including: Blood, Diabetes, Molecular Interventions, Journal of Thrombosis and Haemostasis, Thrombosis and Haemostasis, Clinical Pharmacology and Therapeutics, European Journal of Immunology, International Journal of Cancer, Journal of Pharmacology and Experimental Therapeutics, Neurological Research, Journal of Neurosurgery, American Journal of Clinical Pathology, FASEB J, Cell Death Differentiation, PLoS ONE, Clinical Laboratory and Thrombosis. h index 13.

Her main interests are: the study of metabolism in vivo of thromboxane in diseases at high cardiovascular risk, the studies to characterize the underlying causes of the interindividual variability of response to low doses of aspirin in several diseases with high cardiovascular risk such as diabetes and essential thrombocythemia, the study of expression and regulation of cyclooxygenases and prostanoid receptors.

Bianca Rocca, MD, PhD obtained her Medical Degree in 1989, Cum Laude, the PhD in Experimental Oncology in 1995, and Board Certification in Haematology in 1995.

She was Postdoctoral Fellow at the Center for Experimental Therapeutics, University Pennsylvania School of Medicine, Philadelphia, PA, USA (Mentor: Prof. Garret A. FitzGerald; 1995-1998). Between 1999 and 2004 was Clinical Fellow at the Center for Haemorrhagic and Thrombotic Diseases (Catholic University, Rome). Between 2005 and 2008 was Adjunct Professor of Pharmacology, ‘La Sapienza’ School of Medicine (Rome, Italy) and Research Associate at the Center of Excellence on Aging, University of Chieti, Italy. In 2008 was appointed as assistant Professor of Pharmacology at the Institute of Pharmacology (Catholic University of Rome, Italy) and since October 2016 is Associate Professor of Pharmacology in the same Institute.

She has been the Vice-Chairperson (2014-2016) and Chairperson (2016-2018) of the European Society of Cardiology Working Group of Thrombosis. She has been member of Guideline and Position Paper Task Forces within the European Society of Cardiology. She is currently the Immediate Past-Chairperson of the European Society of Cardiology Working Group of Thrombosis and ex officio member of the European Society of Cardiology Working Group of Aorta and Peripheral Vascular Disease. She is member of the Editorial Board of: Diabetes and Vascular Disease Research, European Heart Journal-Cardiovascular Pharmacology, Pharmacology Research & Perspectives.

She has co-authored over 100 articles in peer-reviewed journals, 9 book chapters, and has manuscripts in prestigious journals such as: Nature Medicine, Science, Blood, Circulation, Journal of Clinical Investigation, Proceedings of the National Academy of Science, Journal of Immunology, Annals of Internal Medicine, Arterosclerosis Thrombosis and Vascular Biology, Molecular Interventions, Nature Clinical Practice in Cardiovascular Medicine, Journal of the American College of Cardiology, Journal of Biological Chemistry, FASEB Journal, European Heart Journal, Diabetes. Her H-index is 42.
 

V. Publications (2013-present)

Patrono C. Gustav Born and life as "a series of ripples widening out from an original centre". Platelets. 2018 Oct 30:1-2. doi: 10.1080/09537104.2018.1535289. [Epub ahead of print]
Patrignani P, Patrono C. Aspirin, platelet inhibition and cancer prevention. Platelets. 2018 Jul 9:1-7. doi: 10.1080/09537104.2018.1492105. [Epub ahead of print]
De Stefano V, Rocca B, Tosetto A, Soldati D, Petrucci G, Beggiato E, Bertozzi I, Betti S, Carli G, Carpenedo M, Cattaneo D, Cavalca V, Dragani A, Elli E, Finazzi G, Iurlo A, Lanzarone G, Lissandrini L, Palandri F, Paoli C, Rambaldi A, Ranalli P, Randi ML, Ricco A, Rossi E, Ruggeri M, Specchia G, Timillero A, Turnu L, Vianelli N, Vannucchi AM, Rodeghiero F, Patrono C.The Aspirin Regimens in Essential Thrombocythemia (ARES) phase II randomized trial design: Implementation of the serum thromboxane B2 assay as an evaluation tool of different aspirin dosing regimens in the clinical setting. Blood Cancer J. 2018 ;8(6):49.
Scally B, Emberson JR, Spata E, Reith C, Davies K, Halls H, Holland L, Wilson K, Bhala N, Hawkey C, Hochberg M, Hunt R, Laine L, Lanas A, Patrono C, Baigent C. Effects of gastroprotectant drugs for the prevention and treatment of peptic ulcer disease and its complications: a meta-analysis of randomised trials. Lancet Gastroenterol Hepatol. 2018 ;3(4):231-241.
Borst O, Münzer P, Alnaggar N, Geue S, Tegtmeyer R, Rath D, Droppa M, Seizer P, Heitmeier S, Heemskerk JWM, Jennings LK, Storey RF, Angiolillo DJ, Rocca B, Spronk H, Ten Cate H, Gawaz M, Geisler T. Inhibitory mechanisms of very low-dose rivaroxaban in non-ST-elevation myocardial infarction. Blood Adv. 2018;2(6):715-730.
Rocca B, Fox KAA, Ajjan RA, Andreotti F, Baigent C, Collet JP, Grove EL, Halvorsen S, Huber K, Morais J, Patrono C, Rubboli A, Seljeflot I, Sibbing D, Siegbahn A, Ten Berg J, Vilahur G, Verheugt FWA, Wallentin L, Weiss TW, Wojta J, Storey RF. Antithrombotic therapy and body mass: an expert position paper of the ESC Working Group on Thrombosis. Eur Heart J. 2018;39(19):1672-1686f.
Spinthakis N, Farag M, Rocca B, Gorog DA. More, More, More: Reducing Thrombosis in Acute Coronary Syndromes Beyond Dual Antiplatelet Therapy-Current Data and Future Directions. J Am Heart Assoc. 2018;26;7(3).
Patrono C. Fighting residual cardiovascular risk in stable patients with atherosclerotic vascular disease: COMPASS in context. Cardiovasc Res. 2017;113(14):e61-e63. 
Patrono C, Morais J, Baigent C, Collet JP, Fitzgerald D, Halvorsen S, Rocca B, Siegbahn A, Storey RF, Vilahur G. Antiplatelet Agents for the Treatment and Prevention of Coronary Atherothrombosis. J Am Coll Cardiol. 2017;70(14):1760-1776..
Cavalca V, Rocca B, Veglia F, Petrucci G, Porro B, Myasoedova V, De Cristofaro R, Turnu L, Bonomi A, Songia P, Cavallotti L, Zanobini M, Camera M, Alamanni F, Parolari A, Patrono C, Tremoli E. On-pump Cardiac Surgery Enhances Platelet Renewal and Impairs Aspirin Pharmacodynamics: Effects of Improved Dosing Regimens. Clin Pharmacol Ther. 2017;102(5):849-858.
Patrono C, Baigent C. Coxibs, Traditional NSAIDs, and Cardiovascular Safety Post-PRECISION: What We Thought We Knew Then and What We Think We Know Now.Clin Pharmacol Ther. 2017; 102(2):238-245.
Patrignani P, Sacco A, Sostres C, Bruno A, Dovizio M, Piazuelo E, Di Francesco L, Contursi A, Zucchelli M, Schiavone S, Tacconelli S, Patrono C, Lanas A. Low-Dose Aspirin Acetylates Cyclooxygenase-1 in Human Colorectal Mucosa: Implications for the Chemoprevention of Colorectal Cancer. Clin Pharmacol Ther. 2017 ;102(1):52-61.
Giaretta A, Rocca B, Di Camillo B, Toffolo GM, Patrono C. In Silico Modeling of the Antiplatelet Pharmacodynamics of Low-dose Aspirin in Health and Disease. Clin Pharmacol Ther. 2017; 102(5):823-831.
Patrono C, Rocca B. Type 2 Diabetes, Obesity, and Aspirin Responsiveness. J Am Coll Cardiol. 2017;69(6):613-615.
Halvorsen S, Storey RF, Rocca B, Sibbing D, Ten Berg J, Grove EL, Weiss TW, Collet JP, Andreotti F, Gulba DC, Lip GYH, Husted S, Vilahur G, Morais J, Verheugt FWA, Lanas A, Al-Shahi Salman R, Steg PG, Huber K; ESC Working Group on Thrombosis. Management of antithrombotic therapy after bleeding in patients with coronary artery disease and/or atrial fibrillation: expert consensus paper of the European Society of Cardiology Working Group on Thrombosis. Eur Heart J. 2017;38(19):1455-1462.
Crea F, Jaffe AS, Collinson PO, Hamm CW, Lindahl B, Mills NL, Thygesen K, Mueller C, Patrono C, Roffi M; 2015 ESC NSTE-ACS Guidelines Task Force. Should the 1h algorithm for rule in and rule out of acute myocardial infarction be used universally? Eur Heart J. 2016;37(44):3316-3323.
Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, Bax JJ, Borger MA, Brotons C, Chew DP, Gencer B, Hasenfuss G, Kjeldsen K, Lancellotti P, Landmesser U, Mehilli J, Mukherjee D, Storey RF, Windecker S. [2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC)]. G Ital Cardiol (Rome). 2016;17(10):831-872.
Petrucci G, Rizzi A, Cavalca V, Habib A, Pitocco D, Veglia F, Ranalli P, Zaccardi F, Pagliaccia F, Tremoli E, Patrono C, Rocca B. Patient-independent variables affecting the assessment of aspirin responsiveness by serum thromboxane measurement. Thromb Haemost. 2016;116(5):891-896.
Russo NW, Petrucci G, Rocca B. Aspirin, stroke and drug-drug interactions. Vascul Pharmacol. 2016;87:14-22
Patrignani P, Patrono C. Aspirin and Cancer. J Am Coll Cardiol. 2016;68(9):967-76.
Rocca B, Husted S. Safety of Antithrombotic Agents in Elderly Patients with Acute Coronary Syndromes. Drugs Aging. 2016;33(4):233-48.
Patrono C. Cardiovascular Effects of Nonsteroidal Anti-inflammatory Drugs. Curr Cardiol Rep. 2016;18(3):25.
 Zaccardi F, Rizzi A, Petrucci G, Ciaffardini F, Tanese L, Pagliaccia F, Cavalca V, Ciminello A, Habib A, Squellerio I, Rizzo P, Tremoli E, Rocca B, Pitocco D, Patrono C. In Vivo Platelet Activation and Aspirin Responsiveness in Type 1 Diabetes. Diabetes. 2016;65(2):503-9.
 Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, Bax JJ, Borger MA, Brotons C, Chew DP, Gencer B, Hasenfuss G, Kjeldsen K, Lancellotti P, Landmesser U, Mehilli J, Mukherjee D, Storey RF, Windecker S, Baumgartner H, Gaemperli O, Achenbach S, Agewall S, Badimon L, Baigent C, Bueno H, Bugiardini R, Carerj S, Casselman F, Cuisset T, Erol Ç, Fitzsimons D, Halle M, Hamm C, Hildick-Smith D, Huber K, Iliodromitis E, James S,Lewis BS, Lip GY, Piepoli MF, Richter D, Rosemann T, Sechtem U, Steg PG, Vrints C, Luis Zamorano J. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC).Eur Heart J. 2016;37(3):267-315.
 Santilli F, Davì G, Patrono C. Homocysteine, methylenetetrahydrofolate reductase, folate status and atherothrombosis: A mechanistic and clinical perspective. Vascul Pharmacol. 2016;78:1-9.
 Rocca B, Patrono C. Platelet progenitors: the hidden drug target. Eur Heart J. 2015;36(45):3211-3
 Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, Bax JJ, Borger MA, Brotons C, Chew DP, Gencer B, Hasenfuss G, Kjeldsen K, Lancellotti P, Landmesser U, Mehilli J, Mukherjee D, Storey RF, Windecker S. [2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation]. Kardiol Pol. 2015;73(12):1207-94.
 Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, Bax JJ, Borger MA, Brotons C, Chew DP, Gencer B, Hasenfuss G, Kjeldsen K, Lancellotti P, Landmesser U, Mehilli J, Mukherjee D, Storey RF, Windecker S. 2015 ESC Guidelines for the Management of Acute Coronary Syndromes in Patients Presenting Without Persistent ST-segment Elevation. Rev Esp Cardiol (Engl Ed). 2015;68(12):1125.
 Andreotti F, Rocca B, Husted S, Ajjan RA, ten Berg J, Cattaneo M, Collet JP, De Caterina R, Fox KA, Halvorsen S, Huber K, Hylek EM, Lip GY, Montalescot G, Morais J, Patrono C, Verheugt FW, Wallentin L, Weiss TW, Storey RF; ESC Thrombosis Working Group. Antithrombotic therapy in the elderly: expert position paper of the European Society of Cardiology Working Group on Thrombosis. Eur Heart J. 2015;36(46):3238-49.
 Barbieri SS, Petrucci G, Tarantino E, Amadio P, Rocca B, Pesce M, Machlus KR, Ranelletti FO, Gianellini S, Weksler B, Italiano JE Jr, Tremoli E. Abnormal megakaryopoiesis and platelet function in cyclooxygenase-2-deficient mice. Thromb Haemost. 2015;114(6):1218-29.
 Collet JP, Roffi M, Mueller C, Valgimigli M, Patrono C, Baumgartner H, Gaemperli O, Zamorano JL. Questions and answers on antithrombotic therapy: a companion document of the 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevaon†. Eur Heart J. 2015. pii: ehv407.
 Mueller C, Patrono C, Valgimigli M, Collet JP, Roffi M. Questions and answers on diagnosis and risk assessment: a companion document of the 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevaon†. Eur Heart J. 2015 . pii: ehv409.
 Valgimigli M, Patrono C, Collet JP, Mueller C, Roffi M. Questions and answers on coronary revascularization: a companion document of the 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J. 2015. pii: ehv408.
 Patrono C. The Multifaceted Clinical Readouts of Platelet Inhibition by Low-Dose Aspirin. J Am Coll Cardiol. 2015;66(1):74-85.
 Lancellotti S, Dragani A, Ranalli P, Petrucci G, Basso M, Tartaglione R, Rocca B, De Cristofaro R. Qualitative and quantitative modifications of von Willebrand factor in patients with essential thrombocythemia and controlled platelet count. J Thromb Haemost. 2015;13(7):1226-37.
 Zaccardi F, Rocca B, Pitocco D, Tanese L, Rizzi A, Ghirlanda G. Platelet mean volume, distribution width, and count in type 2 diabetes, impaired fasting glucose, and metabolic syndrome: a meta-analysis. Diabetes Metab Res Rev. 2015;31(4):402-10.
 Patrignani P, Patrono C. Cyclooxygenase inhibitors: From pharmacology to clinical read-outs. Biochim Biophys Acta. 2015;1851(4):422-32.
 Patrono C. Role of clinical pharmacology in the development of antiplatelet drugs. Clin Ther. 2014 1;36(12):2096-111.
 Patrignani P, Tacconelli S, Piazuelo E, Di Francesco L, Dovizio M, Sostres C, Marcantoni E, Guillem-Llobat P, Del Boccio P, Zucchelli M, Patrono C, Lanas A. Reappraisal of the clinical pharmacology of low-dose aspirin by comparing novel direct and traditional indirect biomarkers of drug action. J Thromb Haemost. 2014;12(8):1320-30.
 Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC); European Association for the Study of Diabetes (EASD). ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD - summary. Diab Vasc Dis Res. 2014;11(3):133-73. .
 Pagliaccia F, Habib A, Pitocco D, Petrucci G, Zaccardi F, Di Stasio E, Rocca B. Stability of urinary thromboxane A2 metabolites and adaptation of the extraction method to small urine volume. Clin Lab. 2014;60(1):105-11
 Cavalca V, Rocca B, Squellerio I, Dragani A, Veglia F, Pagliaccia F, Porro B, Barbieri SS, Tremoli E, Patrono C. In vivo prostacyclin biosynthesis and effects of different aspirin regimens in patients with essential thrombocythaemia. Thromb Haemost.2014;112(1):118-27.
 Patrono C, Baigent C. Nonsteroidal anti-inflammatory drugs and the heart. Circulation.2014;129(8):907-16.